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15.2) T.Nigra,PV,Deep mycosis

Posted by Dr.Md.Hadiuzzaman on February 6, 2013 at 12:40 AM

Tinea nigra

Hortaea werneckii (formerly Phaeoannellomyces werneckii) is a black yeast-like hyphomycete that is widely distributed in hot, humid environments. The organism is common in the tropics. In the US, the infection is commonly seen along the Gulf coast. New taxonomic analysis has led some to classify Cladosporium castellanii as the etiological agent of tinea nigra in humans and confirmed that this fungus is the same as Stenella araguata.

Tinea nigra presents as one or several brown or black spots on the palms or soles. The lesions may be mistaken for nevi or melanoma. The pigment is confined to the stratum corneum and scrapes off easily. Dermoscopy has also been used to differentiate the lesions from melanocytic tumors. The fungus can easily be demonstrated by means of KOH or culture. In KOH preparations, the hyphae appear brown or golden in color. Young colonies are glossy, black, and yeast-like, but older colonies are filamentous and grayish. The pigment produced by the fungal hyphae is melanin. Culture will identify the organism, and PCR can be useful for rapid identification of H. werneckii.

Topical imidazoles and allylamines, such as clotrimazole, miconazole, ketoconazole, sulconazole, econazole, and terbinafine, have been reported as effective. Griseofulvin is not effective. Simply shaving away the superficial epidermis with a blade is frequently both diagnostic and curative.

Piedra (trichosporosis)

In black piedra, dark, pinhead to pebble-sized formations occur on the hairs of the scalp, brows, lashes, or beard. These nodules are distributed irregularly along the length of the shaft. White piedra is commonly caused by T. beigelii or Trichosporon inkin, and occurs more commonly in temperate climates. Based on molecular analysis, the taxon T. beigelii has been replaced by several species. A synergistic corynebacterial infection is often present in white piedra, as demonstrated by culture and electron microscopy. T. beigelii has also been implicated as a cause of onychomycosis. T. inkin is implicated as an etiologic agent of pubic white piedra. Trichosporon asahii causes white piedra and onychomycosis, and has been isolated from black piedra. Trichosporon spp can also cause disseminated disease in immunosuppressed patients, and T. asahii has produced disseminated cutaneous infections in immunocompetent hosts. In white piedra, patients present with yellow or beige-colored, soft, slimy sheaths coating the hair shafts (Fig. 15-17). The sheaths are composed of hyphae, arthrospores, and bacteria. The culture shows cream-colored, soft colonies composed of blastospores and septate hyphae, which fragment into arthrospores.

Black piedra, usually caused by Piedraia hortai, occurs mostly in the tropics, especially in South America and Asia. The nodelike masses in KOH preparations show numerous oval asci containing 2–8 ascospores and mycelium. Cultures produce black colonies composed of hyphae and chlamydospores.

Treatment may be accomplished by cutting or shaving the hair, but this may not be acceptable to the patient. Oral and topical terbinafine have been effective in black piedra. For white piedra, oral itraconazole, topical imidazoles, ciclopirox olamine, 2% selenium sulfide, 6% precipitated sulfur in petrolatum, chlorhexidine solutions, Castellani paint, zinc pyrithione, amphotericin B lotion, and 2–10% glutaraldehyde have all been used successfully. Unfortunately, the recurrence rate is high. Spontaneous remissions are sometimes observed.

Tinea versicolor (pityriasis versicolor)

Tinea versicolor is caused by Malassezia furfur and related fungi. The yeast phase of this organism is classified as Pityrosporum orbiculare. The genus includes 12 lipid-dependent species and a single non lipid-dependent species (Malassezia pachydermatis), that colonizes the skin and mucosal sites of healthy cats and dogs. These organisms are part of the normal follicular flora. They produce skin lesions when they grow in the hyphal phase. Tinea versicolor commonly presents as hypo- or hyperpigmented coalescing scaly macules on the trunk and upper arms (Fig. 15-18). Pink, atrophic, and trichrome variants exist and can produce striking clinical pictures. The eruption is more common during the summer months, and favors oily areas of skin. Sites of predilection are the sternal region and the sides of the chest, abdomen, back, pubis, neck, and intertriginous areas. Mild itching and inflammation about the patches may be present. In some instances many follicular papules are present. The face and scalp may be affected. Facial lesions occur fairly commonly in infants and immunocompromised patients. The disease may even occur on the scalp, palms, and soles. Penile lesions may occur as well, and the organism is commonly isolated from patients with balanoposthitis.

In hypopigmented tinea versicolor, abnormally small and poorly melanized melanosomes are produced, and are not transferred to keratinocytes properly. This becomes most conspicuous in dark-skinned people. This hypopigmentation may persist for weeks or months after the fungal disease is cured unless an effort is made to regain the lost pigmentation through UV exposure.




The fungus is easily demonstrated in scrapings of the profuse scales that cover the lesions. Tape stripping of the lesions can also be performed. Microscopically, there are short, thick fungal hyphae and large numbers of variously sized spores. This combination of strands of mycelium and numerous spores is commonly referred to as “spaghetti and meatballs.” The fungus can be highlighted by a variety of stains, including Parker blue–black ink (mixed 1 : 1 with 20% KOH) and 1% Chicago sky blue 6B with 8% KOH. Identification by culture requires lipid enrichment of the media, and is rarely done to establish the diagnosis. Wood's light examination accentuates pigment changes, and may demonstrate yellow–green fluorescence of the lesions in adjacent follicles.

Biopsy will demonstrate a thick basket-weave stratum corneum with hyphae and spores. In the atrophic variant, epidermal colonization with hyphae and spores is accompanied by effacement of the rete ridges, subepidermal fibroplasia, pigment incontinence, and elastolysis.

Differential diagnosis

Tinea versicolor must be differentiated from seborrheic dermatitis, pityriasis rosea, pityriasis rubra pilaris, pityriasis alba, Hansen's disease, syphilis, and vitiligo. In the atrophic variant, the lesions may suggest parapsoriasis, mycosis fungoides, anetoderma, lupus erythematosus, or steroid atrophy.

The diagnosis in all forms of tinea versicolor is generally easily established by KOH examination. In seborrheic dermatitis the patches have an erythematous yellowish tint and the scales are soft and greasy, whereas in tinea versicolor the scales are furfuraceous (fluffy). Macular syphilid consists of faint pink lesions, less than 1 cm in diameter, irregularly round or oval, which are distributed principally on the nape, sides of the trunk, and flexor aspects of the extremities. They are slightly indurated with a peripheral scale, and may be copper-colored. There may be general adenopathy. Serologic tests are positive in this phase of syphilis, but prozone reactions may occur, and the serum may have to be diluted.

TreatmentImidazoles, triazoles, selenium sulfide, ciclopirox olamine, zinc pyrithione, sulfur preparations, salicylic acid preparations, propylene glycol, and benzoyl peroxide have been used successfully as topical agents. Selenium sulfide lotion is very cost-effective and can be applied daily for a week, washed off after 10 min. It is also effective in a single overnight application. This can be repeated monthly as prophylaxis. The scalp can be shampooed monthly with selenium sulfide to reduce scalp colonization. Zinc pyrithione soap is also cost-effective and well tolerated for treatment and prophylaxis.

Ketoconazole, in 400 mg doses repeated at monthly intervals, is very effective. Oral itraconazole, 200 mg once a day for 7 days, is effective and can be followed by prophylactic treatment with itraconazole, 200 mg twice a day on 1 day a month. In a study of 50 patients, 400 mg single-dose itraconazole was shown to be equivalent to 200 mg/day itraconazole for 7 days. Fluconazole, 400 mg once, may also be effective, and can be repeated at monthly intervals. In a study of 128 patients, weekly dosing with two 150 mg capsules of fluconazole for 2 weeks was equivalent to weekly dosing of two 200 mg tablets of ketoconazole for 2 weeks. The effect of a single dose, not repeated in 2 weeks, was not assessed in this study, and may have proved just as effective. Although terbinafine has been shown to be ineffective via the oral route, it is effective topically. Twice a day applications are superior to once a day applications. Alternatively, 5-aminolevulinic acid photodynamic therapy has been reported as effective.

Patients should be informed that the hypo- and hyperpigmentation will take time to resolve and is not a sign of treatment failure. Relapse is likely if prophylactic doses are not given occasionally, but many options are available for prophylactic treatment. After initial therapy, patients may prefer weekly washing with a topical zinc pyrithione bar, single overnight applications of selenium sulfide, ketoconazole, econazole or bifonazole shampoo every 30–60 days, or monthly oral therapy.

Pityrosporum folliculitis

Pityrosporum folliculitis has been a controversial entity, but its prompt response to antifungal agents suggests that Pityrosporum yeast is indeed pathogenic. Criteria for diagnosis include characteristic morphology, demonstration of yellow–green Wood's light fluorescence of the papules or demonstration of Pityrosporum yeast in smears or biopsies, and prompt response to antifungal treatment. Lesions tend to be chronic, moderately itchy, dome-shaped, follicular papules and tiny pustules involving the upper back and adjacent areas. The face and scalp may be involved, and the lesions are sometimes found in association with either tinea versicolor or seborrheic dermatitis. Pityrosporum folliculitis is more common in organ or marrow transplant recipients. As Pityrosporum yeast is normally part of the follicular flora, alterations in flora may favour uncontrolled growth of the yeast. One such instance occurs when Propionibacterium acnes is suppressed by tetracycline therapy.

The eruption responds to oral fluconazole, 400 mg once; ketoconazole, 400 mg once; or itraconazole, 200 mg/day for 5–7 days. Topical therapy with 2.5% selenium sulfide applied overnight is also generally effective. Other treatments include 30–50% propylene glycol in water, and topical imidazole creams. Relapses are common, but prophylaxis may be successful with monthly applications of selenium sulfide or maintenance doses of topical econazole.

The deep mycoses

Most deep cutaneous fungal infections are a manifestation of systemic infection from inhalation of aeorosolized fungus. When primary infection is introduced directly into the skin from puncture wounds, abrasions, or other trauma, a chancriform or verrucous lesion will form that may be accompanied by secondary lymphangitis. Chest radiographs should be taken when investigating patients with deep mycoses except for the classic inoculation types, such as sporotrichosis, mycetoma, chromoblastomycosis, and phaeohyphomycosis.


Coccidioidomycosis is also known as coccidioidal granuloma, valley fever, and San Joaquin valley fever.

Primary pulmonary coccidioidomycosis

Inhalation of Coccidioides immitis, followed by an incubation period of 10 days to several weeks, produces a respiratory infection that may be mild, with only a low-grade fever resembling a flulike illness. Approximately 60% of infected persons are entirely asymptomatic. Severe symptoms of chills, high fever, night sweats, severe headache, backache, and malaise may ensue in a minority. A large percentage of patients show lung changes on roentgenographic examination. These include hilar adenopathy, peribronchial infiltration, or an infiltrate compatible with bronchopneumonia. At the time of onset a generalized maculopapular eruption may be present, which may be confused with a drug eruption, measles, or scarlet fever.

Within a few weeks the pulmonary symptoms subside. In about 30% of women and in 15% of men, allergic skin manifestations appear in the form of erythema nodosum over the shins and sometimes over the thighs, hips, and buttocks. These tender lesions may become confluent, gradually turn from purple to brown, and then disappear in about 3 weeks. Erythema nodosum is a favorable prognostic sign and occurs mostly in white individuals with transient self-limited disease. Sometimes erythema multiforme may develop in a similar clinical setting.

Although valley fever is usually self-limited and patients recover spontaneously, a small percentage steadily progress into the chronic, progressive, disseminated form. The propensity for disseminated disease is several-fold higher in Hispanics and Native Americans, and many times higher for African Americans, Filipinos, and Vietnamese. In women, pregnancy may predispose to systemic disease. Infants, the elderly, persons with blood types B or AB, and immunosuppressed patients, including those with AIDS, are also at increased risk for severe disease.

Disseminated coccidioidomycosis (coccidioidal granuloma)

Dissemination occurs in less than 1% of infections, but its incidence is heavily influenced by the factors listed above. Target organs include the bones, joints, viscera, brain, meninges, and skin. A single organ or multiple organs may be involved.

Skin lesions occur in 15–20% of patients with disseminated disease. They may appear as verrucous nodules (Fig. 15-19), as pink papules resembling basal cell carcinoma, or as subcutaneous abscesses. The face is frequently involved. Some chronic lesions develop into plaques that resemble mycosis fungoides or North American blastomycosis. In patients with AIDS, umbilicated papules may mimic molluscum contagiosum. Umbilicated papules are more commonly associated with cryptococcosis, but can occur with a variety of fungi.



Primary cutaneous coccidioidomycosis

This form occurs rarely, and skin disease should be considered a manifestation of disseminated disease unless there is a definite history of inoculation or a colonized splinter is found in the lesion. Between 1 and 3 weeks following inoculation an indurated nodule develops that may ulcerate. Later, nodules appear along the lymphatic vessels. Spontaneous recovery may result after several weeks, although most patients are treated with systemic agents.

Etiology and pathology

The causative organism, C. immitis, has been isolated from the soil and from vegetation. It is commonly found in the burrows of rodents, often at a depth of about 20 cm. Epidemics occur when the soil is disrupted to a depth of 20 cm or more. This can occur as a result of road work, laying of telephone or electric cable, dust storms, and earthquakes. A large outbreak occurred in 1994 in Ventura County, California, after the Northridge earthquake. Outbreaks occur sporadically in California and Arizona. Outbreaks in military personnel are often related to training in endemic areas.

C. immitis is dimorphous, reproducing brittle mycelia at room temperature, and spherules in tissue. Spherules are unencapsulated with a thick refractile wall and a granular interior. They measure 5–200 µm in diameter, but average 20 µm. Endosporulation can occur, and the organism can resemble Rhinosporidium. Compared to the latter organism, Coccidioides is typically much smaller and more uniform in size. It also lacks the small central nucleus that is uniformly present in non-sporulating Rhinosporidium.


Coccidioides is readily grown at room temperature, and is highly infectious. For this reason, culture of deep fungi should never be attempted in the office setting. Cultures should only be performed in laboratories with biocontainment hoods. The colonies appear on Sabouraud dextrose agar within 2–7 days as small, slightly raised disks penetrating the medium. Older cultures become covered with a dusty layer of aerial hyphae and assume a brownish color with age. In culture, spherical bodies throw out filaments of barrel-shaped arthrospores. Mycelia are branched and septate, 2–8 µm in diameter. PCR primers and a DNA hybridization probe test that targets organism-specific ribosomal RNA show promise for rapid identification.


The disease principally occurs in limited areas in the western hemisphere. The original diagnosis was in a soldier from Argentina, where the disease is endemic in the Gran Chaco area. It is also endemic in northern Mexico, Venezuela, and the southwestern US (the lower Sonoran Life Zone). In highly endemic areas, most residents will have been infected, and new residents have a good chance of becoming infected within 6 months. Very few will develop disseminated disease, although the attack rate has recently increased in both California and Arizona.

Differential diagnosis

Clinically, it is extremely difficult to differentiate this disease from blastomycosis, which it closely resembles. Definite diagnosis depends on serologic testing and the demonstration of C. immitis microscopically, culturally, or by animal inoculation. Guinea pigs inoculated with C. immitis die from the systemic infection, whereas no evidence of infection is apparent after inoculation with Blastomyces. Intradermal testing with coccidioidin has largely been replaced by serologic testing. A positive reaction of the delayed tuberculin type develops early and remains high in those who resist the disease well. A negative skin test occurs with dissemination.


The first widely used skin test, coccidioidin, was developed in the 1940s. In the 1970s, spherulin was found to be more sensitive. Cross-reactions can occur with histoplasmin, blastomycin, and paracoccidioidin. In vitro tests of cellular immunity yield comparable results and skin testing has generally been replaced by serologic testing. Precipitin, latex agglutination, immunodiffusion, and complement fixation serologic tests have been developed. The precipitin, immunodiffusion, enzyme immunoassay (EIA), and latex agglutination tests are useful in very recent infection, since a maximum titer is reached in 1–2 weeks. They permit detection of coccidioidal IgM in early coccidioidomycosis. In later infections, the complement fixation test is useful. In primary coccidioidomycosis the titer is low, whereas in subsequent dissemination there is a rapid rise in titer. When the disease has disseminated, cerebrospinal, synovial, and peritoneal fluid can be tested for coccidioidal antibody. The Coccidioides-specific EIA detects antigenuria in about 70% of patients with coccidioidomycosis and is negative in more than 99% of controls without fungal infections. Cross-reactions with other systemic mycoses occur in 10.7% of patients. An isolated positive EIA IgM usually means disseminated disease.


Amphotericin B is active against the organism, but less toxic drugs are now available. Fluconazole, at doses of 400–800 mg/day, is commonly used. Treatment must be continued for 12 months or longer. Many patients will require ongoing suppressive therapy. In patients infected with HIV, lifetime suppressive doses of 200 mg/day are advised and potent antiretroviral therapy is associated with improved outcomes. In coccidioidomycotic meningitis, fluconazole, 400–600 mg/day, is given indefinitely. Fluconazole and itraconazole have similar efficacies in the treatment of progressive nonmeningeal coccidioidomycosis. In meningeal disease itraconazole is not effective and amphotericin needs to be given intrathecally in addition to intravenously. Liposomal amphotericin is effective in animal models of meningeal disease without the need for intrathecal administration. Newer agents that have activity against C. immitis include voriconazole, caspofungin, and posaconazole. Voriconazole has been used successfully in meningeal disease. Azole resistance has been reported and should be suspected in patients with refractory disease.


Histoplasmosis is caused by inhalation of airborne spores. It may be asymptomatic or cause limited lung disease. Dissemination to other organs, including the skin, occurs in about 1 in 2000 acute infections. Immunodeficiency, old age, and systemic corticosteroids predispose to widespread disease. Cases misdiagnosed as sarcoidosis and treated with corticosteroids have disseminated widely. In disseminated disease, mucous membranes are involved much more commonly than skin. Primary cutaneous disease is exceedingly rare.

Primary pulmonary histoplasmosis

Primary pulmonary histoplasmosis is usually a benign self-limited form of acute pneumonitis characterized by fever, malaise, night sweats, chest pain, cough, and hilar adenopathy. Resolution of the pneumonitis occurs rapidly, and the only residua may be calcifications in the lung and a positive skin test to histoplasmin. However, serious pneumonitis caused by histoplasmosis does occur. Such cases have been reported among cave workers in Mexico and travelers returning from Central America. A chronic pulmonary form may occur in patients with emphysema.

Approximately 10% of patients with acute symptomatic infection develop arthritis and erythema nodosum. During a large midwestern epidemic, about 4% of patients diagnosed with histoplasmosis presented with erythema nodosum. Erythema multiforme has also been described.

Progressive disseminated histoplasmosis

Most patients who develop this severe form are immunocompromised or taking systemic corticosteroids. Leukemia, lymphoma, lupus erythematosus, renal transplantation, or AIDS is a frequent predisposing disease. Cases have also been reported in patients receiving low-dose methotrexate for psoriasis. Approximately 20% have no identifiable risk factor.

The reticuloendothelial system, genitourinary tract, adrenals, gastrointestinal tract, adrenal glands, and heart may be involved. Ulcerations and granulomas of the oronasopharynx are the most common mucocutaneous lesions, occurring in about 20% of patients with disseminated disease (Fig. 15-20). Beginning as solid, indurated plaques, they ulcerate and become deepseated, painful, and secondarily infected. Perianal lesions may also occur.



Skin lesions are present in approximately 6% of patients with dissemination and may be more common in patients with AIDS and in renal transplant recipients. Recently, cases have been reported in association with infliximab therapy. The morphologic patterns are nonspecific and protean, including umbilicated nodules, papules, plaques (Fig. 15-21), and ulcers. Cellulitis may also occur. Abscesses, pyoderma, pustules, and furuncles may be the first lesions on the skin. Demonstration of the organisms is readily made from histologic sections and cultures of the exudate. The most common manifestation in children is purpura. Usually it appears a few days before death and is probably caused by severe involvement of the reticuloendothelial system, with emaciation, chronic fever, and severe gastrointestinal symptoms.



In the HIV-positive population, dyspnea, a platelet count of <100 000 platelets/mm3, and lactate dehydrogenase levels of more than two-fold the upper limit of the normal range are poor prognostic factors, and are independently associated with death during the first 30 days of antifungal treatment.

Primary cutaneous histoplasmosis

This rare entity is characterized by a chancre-type lesion with regional adenopathy. It has been reported on the penis.

African histoplasmosis

This type is caused by Histoplasma duboisii, now classified as a variant of Histoplasma capsulatum. Skin lesions are much more common and include superficial cutaneous granulomas, subcutaneous granulomas, and osteomyelitic lesions with secondary involvement of the skin (cold abscesses). In addition, papular, nodular, circinate, eczematoid, and psoriasiform lesions may be seen. The granulomas are dome-shaped nodules, painless but slightly pruritic. There may be skin and mucous membrane manifestations such as ulcerations of the nose, mouth, pharynx, genitals, and anus. These ulcers are chronic, superficial lesions with no induration or noticeable inflammatory reaction. Erythema nodosum occurs frequently. Emaciation and chronic fevers are common systemic signs.

Etiology and pathology

Histoplasmosis was first discovered in Panama by ST Darling in 1906. It is caused by H. capsulatum, a dimorphic fungus that exists as a soil saprophyte. The organism is frequently found in bat and bird feces.

In tissue there are 2–3 µm round bodies within the cytoplasm of large macrophages. A pseudocapsule surrounds each organism. The organisms bear a striking resemblance to those of leishmaniasis, but lack a kinetoplast and are distributed evenly throughout the cytoplasm, while leishmanial organisms often line up at the periphery of the cell like light bulbs on a movie marquee. Budding forms may rarely be present, and mycelial and pleomorphic budding forms are sometimes seen in cavitary pulmonary disease, endocardial disease, aortic plaques, or skin lesions. Morphologically, these forms resemble Candida more than typical intracellular Histoplasma. On direct examination the organism may be demonstrated in the peripheral blood, sputum, bronchial washings, spinal fluid, sternal marrow, lymph node touch smears, or ulcers when stained with Giemsa, PAS, or Gomori methenamine silver stains. In African histoplasmosis, the organisms are 10–13 µm in diameter and are typically found within multinucleated giant cells.

The mycelial phase may be demonstrated on Sabouraud dextrose agar, Mycosel medium, or brain–heart infusion agar to which blood has been added. A white, fluffy colony is found, with microconidia and echinulate macroconidia. One set of cultures should be inoculated at room temperature to demonstrate the mycelial phase and another at 37°C to produce the yeast phase. In disseminated disease the bone marrow is frequently involved. Blood, urine, and tissue from oral and skin lesions should also be cultured. PCR probes are available for rapid culture confirmation.


Although histoplasmosis occurs throughout the world, it is most common in North America, especially in the central states of the US along the Mississippi River basin. Histoplasmosis is found frequently in river valley areas in the tropical and temperate zones. The Nile River valley seems to be one exception. Besides the Mississippi and Ohio river valleys, it has been found along the Potomac, Delaware, Hudson, and St Lawrence rivers. It has been reported in the major river valleys of South America, Central Africa, and Southeast Asia. The disease is heavily endemic in Puerto Rico and Nicaragua.

Transmission of the disease does not occur between individuals; instead, the infection is contracted from the soil by inhalation of the spores, especially in a dusty atmosphere. Feces of birds and bats contain the fungus. The spores have been demonstrated in the excreta of starlings, chickens, and bats. The disease may be contracted by persons who enter caves inhabited by bats or birds. Epidemics have been reported from exposure to silos, abandoned chicken houses, and storm cellars. Infected people throughout the world number in the many millions.

In an outbreak in Indianapolis in 1978, 488 clinically recognized cases occurred, and 55 had disseminated disease. The actual number infected was probably well over 100 000. Nineteen died, none of whom were under the age of 1. Fatal or disseminated infections occurred in 74% of immunosuppressed persons, compared with 6.5% of those without immunosuppression. Age over 54 was a worse prognostic factor than chronic lung disease in nonimmunosuppressed persons. Disseminated histoplasmosis is seen as an opportunistic infection in HIV-infected individuals, reflecting impaired cellular immune function.


The best diagnostic test has been the urinary enzyme-linked immunosorbent assay (ELISA), but PCR assays are now available and demonstrate excellent sensitivity. Serologic testing for antibodies requires that the patient has normal immune responsiveness and is further limited by a high rate of false-positives and false-negatives, especially cross-reactions with blastomycosis. The complement fixation test, when positive at a titer of 1 : 32 or greater, indicates active or recent infection. Because of the limitations of serologic studies, culture remains the gold standard.


Whereas minimal disease heals spontaneously in the majority of cases, moderate to severe disease requires therapy. Amphotericin B is the treatment of choice in severely ill patients and all immunocompromised patients. In patients infected with HIV a suppressive dose of 200 mg/day of itraconazole follows the intravenous amphotericin. Itraconazole, 200 mg/day for 9 months, may be given for moderate disease in immunocompetent patients. Most patients initially treated with amphotericin B respond quickly and can be switched to itraconazole.


Cryptococcosis generally begins as a pulmonary infection and remains localized to the lung in 90% of cases. In the remaining 10% the organisms hematogenously disseminate to other organs, with the central nervous system (CNS) and the skin the two most common secondary sites. Patients in the latter group are usually immunocompromised or debilitated. The incidence of dissemination is much higher in patients with AIDS, occurring in up to 50% of this population.

Primary pulmonary cryptococcosis infection may be so mild that the symptoms of fever, cough, and pain may be absent. On the other hand, some cases may be severe enough to cause death. Radiographic studies will reveal disease at this stage.

When dissemination occurs, the organism has a special affinity for the CNS. It is the most common cause of mycotic meningitis. There may be restlessness, hallucinations, depression, severe headache, vertigo, nausea and vomiting, nuchal rigidity, epileptiform seizures, and symptoms of intraocular hypertension. Other organs, such as the liver, skin, spleen, myocardium, and skeletal system, as well as the lymph nodes, may be involved. Disseminated cryptococcosis can present in many organ systems; hepatitis, osteomyelitis, prostatitis, pyelonephritis, peritonitis, and skin involvement have all been reported as initial manifestations of disease. The incidence of skin involvement in cases of cryptococcosis is between 10% and 15%, although it is lower in the HIV-infected population. Cutaneous lesions may precede overt systemic disease by 2–8 months.

Skin infection with cryptococcosis occurs most frequently on the head and neck. A variety of morphologic lesions have been reported, including subcutaneous swellings, abscesses, blisters, tumorlike masses, molluscum contagiosum-like lesions, draining sinuses, ulcers, eczematous plaques, granulomas, papules, nodules, pustules, acneiform lesions, plaques, and cellulitis (Fig. 15-22). Presentation as an isolated penile plaque has been reported. Approximately 50% of patients with HIV will develop molluscum contagiosum-like lesions. In these patients there is often a central hemorrhagic crust. Lesions may first become evident in HIV-infected patients during highly active antiretroviral therapy (HAART). Solitary cutaneous lesions and indolent cellulitis may be the presenting signs of disseminated disease.

Primary inoculation cryptococcosis is a very rare disease. To establish the diagnosis, there should be a clear history of implantation or a foreign body found in association with the organism. Usually, primary inoculation disease presents as a solitary skin lesion on an exposed area, frequently in the form of a whitlow. Risk factors include outdoor activities and exposure to bird droppings. Cryptococcus neoformans serotype D is more commonly associated with primary cutaneous disease. Although primary cutaneous disease exists, for all practical purposes, identification of cryptococci in the skin indicates disseminated disease with a poor prognosis, and it requires a search for other sites of involvement.



Etiology and pathology

The causative organism is C. neoformans. It appears in tissue as a pleomorphic budding yeast. The organisms vary markedly in size and shape, in contrast to most other fungal organisms. The capsule is usually prominent, although it is inversely proportional to the extent of the granulomatous reaction. Generally, the capsule is easily identified in hematoxylin and eosin (H&E) sections, although mucicarmine, methylene blue or alcian blue staining can also be used. Usually, multiple yeast share a common capsule. Cryptococcus stains well with the Fontana–Masson stain for melanin.


Cryptococcosis has a worldwide distribution and affects both humans and animals. The organism has been recovered from human skin, soil, dust, and pigeon droppings. The latter, when deposited on window ledges in large cities, are a source of infection. The patient with disseminated cryptococcosis usually has a concomitant debilitating disease, such as AIDS, cancer, leukemia, lymphoma, renal failure, hepatitis, alveolar proteinosis, severe diabetes mellitus, sarcoidosis, tuberculosis, or silicosis. Long-term oral prednisone or immunosuppressive therapy for chronic illnesses, such as renal transplantation, sarcoidosis, or connective tissue disease, may also be a factor. Cases are being reported in association with anti-tumor necrosis factor (TNF)-α biologics. The portal of entry is the lung. Males outnumber females 2:1. Cryptococcosis is most frequent in persons aged 30–60 years.

Patients with AIDS are particularly at risk for disseminated disease. Cryptococcosis is the fourth leading cause of opportunistic infection and the second most common fungal opportunist, with 5–9% of patients manifesting symptomatic disease. Dissemination occurs in 50% of patients with AIDS; skin involvement is reported to be present in 6% of patients with AIDS.


The latex slide agglutination test is sensitive and specific. It may give false-positives in the presence of rheumatoid factor. Direct microscopic examination and latex agglutination have been used with lesional skin scrapings to aid in rapid diagnosis. The complement fixation test for cryptococcal polysaccharide, the indirect fluorescence test, and the EIA for cryptococcal antigen detection are all helpful, but the last is capable of detecting the presence of antigen earlier and at a lower concentration than the other two tests.


For direct examination, a drop of serum or exudate is placed on a slide and then covered with a coverslip. If examination shows yeast, one drop of 10% KOH can be added to half of the coverslip and one drop of India ink to the other half to demonstrate the capsule.

The organism produces a moist, shiny, white colony on Sabouraud dextrose agar. With aging the culture may turn to a cream and then a tan color. Subcultures from Sabouraud agar may be made on to cornmeal agar, and on to urea medium to aid in distinguishing the yeast from Candida and other yeasts. A commercially available DNA probe detection assay allows rapid culture confirmation.

TreatmentIn seriously ill patients, amphotericin B intravenously initially, followed by fluconazole orally, is standard treatment. In less severely ill non-AIDS patients, fluconazole 400–600 mg/day for 8–10 weeks, may be effective. In non-AIDS meningitis, flucytosine is given in combination with amphotericin B, and in patients infected with HIV fluconazole is given indefinitely at a suppressive dose of 200 mg/day. In one study of AIDS patients suffering from cryptococcal meningitis, 600 mg/day of either fluconazole or itraconazole showed efficacy. The availability of voriconazole has expanded the number of options available. In disease refractory to other drugs, voriconazole has shown a response rate of 38.9%. Caspofungin has limited activity against cryptococcosis.


Sporotrichosis usually occurs as a result of direct inoculation by a thorn, cat's claw, or other minor penetrating injury. The earliest manifestation may be a small nodule which may heal and disappear before the onset of other lesions. In the course of a few weeks nodules generally develop along the draining lymphatics (Fig. 15-25). These lesions are at first small, dusky red, painless, and firm. In time the overlying skin becomes adherent to them and may ulcerate. When the lesions occur on the face, the lymphatic drainage is radial, rather than linear, and secondary nodules occur as rosettes around the primary lesion.

Regional lymphangitic sporotrichosis is the common type, accounting for 75% of cases. Fixed cutaneous sporotrichosis is seen in 20% of cases and is characterized by a solitary ulcer, plaque, or crateriform nodule without regional lymphangitis (Fig. 15-26). It may also present as localized rosacea-like lesions of the face without regional lymphangitis. Increased host resistance, a smaller inoculum, facial location, and variations in strain pathogenicity have all been suggested as reasons for the fixed cutaneous form. The distribution in children is similar to that in adults.

Disseminated disease is the least common form. Factors that predispose to extracutaneous disease include oral prednisone therapy, other immunosuppressive drugs including TNF-α inhibitors, chronic alcoholism, diabetes mellitus, hematologic malignancies, and AIDS. Systemic invasion may produce cutaneous, pulmonary, gastrointestinal, articular, and brain lesions. Arthritis or bone involvement occurs in most cases. The cutaneous lesions are reddish, tender nodules, which soften, form cold abscesses, and eventually suppurate, leaving chronic ulcers or fistulas. These are usually around arthritic joints and the face and scalp, but may occur anywhere on the skin. At times only internal involvement is apparent.



Etiology and pathology

Sporotrichosis is caused by Sporothrix schenckii, a dimorphic fungus that grows in a yeast form at 37°C and in a mycelial form at room temperature. Cutaneous disease typically presents with palisading granulomatous dermatitis surrounding a stellate suppurative abscess. Organisms appear as cigar-shaped yeast in tissue, but are rare in North American cases. In Asian cases of sporotrichosis, the organisms are frequently more numerous. Asteroid bodies and mycelial elements are prevalent in regional lymphangitic sporotrichosis. PCR methods of detection have been developed.


There seems to be no geographic limitation to the occurrence of sporotrichosis. Most often the primary invasion is seen as an occupational disease in gardeners, florists, and laborers following injuries by thorns, straw, or sphagnum moss. The pathogen commonly lives as a saprophyte on grasses, shrubs, and other plants. Carnations, rose bushes, barberry shrubs, and sphagnum moss are common sources. Infection may also be noted after insect stings. High humidity and high temperature favor infection. An epidemic of sporotrichosis among South African diamond miners was ascribed to inoculation of the organism by rubbing against the supporting wooden beams in the mines. Experimentally, it has been produced in many laboratory animals, and spontaneous cases have been observed in horses, mules, dogs, cats, mice, and rats. In cats, sporotrichosis commonly produces disseminated disease. The organism may be found on the claws, and transmitted to humans through cat scratches. Epidemics related to cat exposure have been documented.


On Sabouraud agar a moist, white colony develops within 3–7 days. The surface becomes wrinkled and folded. Later the culture turns tan and, ultimately, black, as the organism is capable of producing melanin. In slide culture preparations the colony shows septate branching mycelia. Conidia are found in clusters or in sleevelike arrangements on delicate sterigmata. If the culture is grown at 37°C, grayish-yellow, velvety yeast-like colonies are produced. Cigar-shaped, round, oval, and budding cells, hyphae, and conidia may be seen microscopically.


Culture extracts from S. schenckii, known as sporotrichins, will produce a delayed tuberculin-type reaction in persons who have had sporotrichosis. The test is fairly reliable, but only indicates previous exposure. Agglutination testing has been developed, but clinical diagnosis, biopsy, and culture remain the most common means of establishing a diagnosis.

Differential diagnosis

Demonstration by culture establishes the diagnosis, and it is important to differentiate sporotrichosis from other lymphangitic infections. Atypical mycobacteriosis (especially Mycobacterium marinum), leishmaniasis, and nocardiosis all produce lymphangitic spread. In contrast, tuberculosis, cat-scratch disease, tularemia, glanders, melioidosis, lymphogranuloma venereum, and anthrax produce ulceroglandular syndromes (an ulcer with regional lymphadenopathy rather than an ulcer with nodules along the lymphatic vessels).

TreatmentItraconazole is effective at a dose of 100–200 mg/day for several months. Pulse dosing has also been used, with 400 mg/day for 1 week with a 3-week break, repeated until lesions are clear. Some data also suggest that terbinafine at a dose of 250 mg per day is effective, although the mean time for clearance in one study was in the order of 14 weeks. For cutaneous forms, potassium iodide, in doses of 2–6 g/day, remains an effective and inexpensive therapeutic option, and may be effective in cases where itraconazole therapy fails. Decades of experience demonstrate its effectiveness despite the absence of published high-level evidence. Iodide therapy usually requires 6–12 weeks of treatment. Generally, it is best to begin with five drops of the saturated solution in grapefruit or orange juice three times a day after meals. The drops can also be put in milk, but strong-flavored citrus juices are better at masking the taste. The dose should be gradually increased until 30–50 drops are taken three times a day. The drug is not suitable for pregnant women. Adverse effects of iodide therapy include nausea, vomiting, parotid swelling, acneiform rash, coryza, sneezing, swelling of the eyelids, hypothyroidism, a brassy taste, increased lacrimation and salivation, flares of psoriasis, and occasionally, depression. Most of the side effects can be controlled by stopping the drug for a few days and reinstituting therapy at a reduced dosage. Application of local hot compresses, hot packs, or a heating pad twice a day has been advocated as a useful adjunct, as S. schenckii is intolerant to temperatures above 38.5°C (101°F).

In adult disseminated cases, itraconazole, 300 mg twice a day for 6 months, followed by 200 mg twice a day, is the treatment of choice. In children, the drug is dosed based on weight and therapeutic response. The drug may have to be continued for many months. Amphotericin B, 0.5 mg/kg/day, is an alternative, but sensitivity to this is strain-dependent. S. schenckii is more sensitive to itraconazole than voriconazole, but the latter drug may also represent a therapeutic option.


Chromoblastomycosis usually affects one of the lower extremities (Fig. 15-27). It occurs as a result of direct inoculation of the organism into the skin. As a rule, lesions begin as a small, pink, scaly papule or warty growth on some part of the foot or lower leg, then slowly spread through direct extension and satellite lesions. With time, lesions develop a verrucous or nodular border and central atrophy and scarring. Small lesions may resemble common warts. Regional lymphadenitis may occur as a result of secondary bacterial infection, and a lymphangitic pattern of infection has been reported. In rare instances, the disease begins on an upper extremity or the face. Longitudinal melanonychia has been reported. Rarely, CNS involvement has been reported, both with and without associated skin lesions.

There is a 4:1 male predominance, and farmers account for almost 75% of patients with the disease. The disease is slowly progressive, and the average time between the appearance of lesions and diagnosis is almost 15 years. Lesions occur at sites of minor trauma. A thorn injury is remembered in about 16% of patients. Squamous cell carcinoma may occur in long-standing cases.



Etiology and pathology

Most cases are caused by one of five dematiaceous fungi. Fonsecaea pedrosoi is the most common cause, and accounts for 90% or more of the cases reported in South America. It has also been reported as the most common cause in other parts of the world. Other agents include Phialophora verrucosa, Fonsecaea compacta, Cladosporium carrionii, and Rhinocladiella aquaspersa. Exophiala spinifera and Exophiala jeanselmei have been reported in isolated cases. Patients may have more than one organism, and cutaneous lesions caused by both paracoccidioidomycosis and chromoblastomycosis have been reported in the same patient. Patients may also have chromoblastomycosis concurrently with mycetoma or invasive phaeohyphomycosis. CNS lesions have been associated with Cladosporium trichoides (Xylohypha or Cladophialophora bantiana), as well as other organisms to include F. pedrosoi. Most of the reported cases are really phaeohyphomycosis, rather than chromoblastomycosis, because the organism grows in the hyphal form.

Histopathologically, lesions are characterized by pseudoepitheliomatous hyperplasia with intraepidermal abscess, a dermal granulomatous reaction, and the presence of pigmented fungal sclerotic bodies. The fungi often appear in clusters that reproduce by equatorial septation, rather than by budding. The presence of sclerotic bodies (Medlar bodies, “copper pennies”) rather than hyphae distinguishes the infection from invasive phaeohyphomycosis. The organisms are often seen in association with an embedded splinter. Medlar bodies are usually easily identified, but Ziehl–Neelsen and Wade–Fite stains have also been used to identify the pathogenic organisms, as has duplex PCR.

Staining for fungal antigens has demonstrated that they accumulate in macrophages and occasionally in factor XIIIa-positive dendrocytes or Langerhans cells. The immune response to the organism appears to affect the clinical and histologic presentation. Patients with verrucous plaques demonstrate a type T-helper 2 (Th2) immunologic response, while those with erythematous atrophic plaque have a type Th1 response. Immune stimulation with recombinant IL-12 or anti-IL-10 can restore an antigen-specific Th1-type response in monocytes from patients with severe disease.


Chromoblastomycosis was first recognized in Brazil by Pedroso in 1911. Since then it has been found in other parts of South America and the Caribbean, Madagascar, South Asia, East Asia, the US, Russia, and many other countries. Barefooted farm workers bear the largest burden of infection. Trauma from wood products and soil exposure results in implantation of the organism, and dissemination is rare.


The microorganisms produce black, slowly growing, heaped-up colonies. The genera differ according to the type of conidiophore produced. All produce melanin.


Treatment is difficult, and the disease often affects those who can ill afford medication. In some series, only about 30% of patients were cured, although almost 60% improved. About 10% fail therapy outright, and recrudescence of the disease is noted in more than 40% of patients. Smaller lesions of chromoblastomycosis are best treated by surgical excision or cryotherapy. In one study of 22 patients, the number of cryosurgeries varied from 1 to 22, and treatment lasted for up to 126 months. Only three patients did not respond. If the lesions are extensive, itraconazole, 100 mg/day or more, is given for at least 18 months. Terbinafine, 500 mg/day for 6–12 months, has been effective in some patients. In refractory cases, itraconazole may be combined with cryotherapy, application of heat (local hyperthermia), or CO2 laser vaporization. Alternate-week therapy with itraconazole and terbinafine has also been reported. Local hyperthermia alone has been reported as effective in some cases, and has been combined with CO2 laser vaporization. Despite these options, some lesions remain resistant, and amputation may be unavoidable in some patients. Combination amphotericin B and itraconazole has been used in resistant cases, as has isolated limb infusion with melphalan and actinomycin D.


Mycetoma, also known as Madura foot and maduromycosis, is a chronic, granulomatous, subcutaneous, inflammatory disease caused by filamentous bacteria (actinomycetoma) or true fungi (eumycetoma). The organisms enter the skin by traumatic inoculation. Both forms of mycetoma present as progressive subcutaneous swelling with sinus tracts that discharge grains (Fig. 15-29).

The disease progresses slowly. Mycetomas generally begin on the instep or the toe webs. The lesion is commonly relatively painless, nontender, and firm. The overlying skin may be normal or attached to the underlying tumor. Mature lesions often have nodules and draining sinuses. Not only the skin and subcutaneous tissues, but also the underlying fascia and bone are involved. Other parts of the body, such as the hands, arms, chest, jaw, and buttocks, may be involved. Exposed sites are most common, and lesions in covered areas are nearly always actinomycetomas.



Etiology and pathology

Mycetoma is divided into actinomycetoma, produced by bacteria, and eumycetoma, produced by true fungi. Actinomycetomas are caused by Nocardia, Actinomadura, or Actinomyces spp. Eumycetomas are caused by true fungi, including pigmented fungi such as Madurella spp, and hyaline fungi such as Pseudallescheria and Acremonium (Cephalosporium). Organisms include Pseudallescheria boydii (which may occasionally disseminate as the anamorph or asexual form, Scedosporium apiospermum), Madurella grisea, Madurella mycetomatis, Acremonium falciforme, Acremonium recifei, Leptosphaeria senegalensis, E. jeanselmei, Pyrenochaeta romeri, and Phialophora verrucosa. Examples of actinomycetomas are those caused by Nocardia asteroides, Nocardia brasiliensis, Nocardia caviae, Actinomadura madurae, Actinomadura pelletieri, Actinomyces israelii, and Streptomyces somaliensis. A. israelii is the major cause of lumpy jaw, a form of mycetoma.

Almost all actinomycetomas produce light-colored grains, as do hyaline fungi. The list of light-grain organisms includes A. israelii, A. madurae, Nocardia spp, S. somaliensis, P. boydii, Acremonium spp, Aspergillus nidulans, Fusarium spp, and Neotestudina rosatii. Red grains are usually produced by A. pelletieri, although red pigment-producing colonies that differed from this organism (they were positive for casein hydrolysis and negative for nitrate reduction and hydrolysis tests of xanthine, hypoxanthine, and tyrosine) have been described and provisionally identified as Actinomadura vinacea. Pigmented fungi produce dark grains. These organisms include M. grisea, M. mycetomatis, Curvularia geniculata, Helminthosporium speciferum, L. senegalensis, E. jeanselmei, P. verrucosa, and P. romeri.

Histologic sections demonstrate stellate abscesses containing grains. Gram stain of an actinomycotic grain shows Gram-positive, thin filaments, 1–2 µm thick, embedded in a Gram-negative amorphous matrix. Club formation in the periphery of a grain may be seen. Special stains for demonstration of fungi, such as PAS and Gomori methenamine silver, will clearly show hyphae and other fungal structures within the grain. Hyphae of 2–5 µm in thickness suggest true fungal mycetoma.


The mycetoma belt stretches between the latitudes of 15° south and 30° north. Relatively arid areas have higher rates of infection than humid areas. In the western hemisphere the incidence is highest in Mexico, followed by Venezuela and Argentina. In Africa it is found most frequently in Senegal, Sudan, and Somalia. Mycetomas are also reported in large numbers in India. Actinomycetomas outnumber eumycetomas by 3:1, which is a blessing as the former is much more responsive to therapy. The male to female ratio varies from 2:1 to 5:1.


For true fungi (eumycetoma), cultures are made from the grains on Sabouraud dextrose agar containing 0.5% yeast extract and suitable antibiotics. Cultures should be incubated at 37°C and room temperature. For actinomycetes grains, culture should be made in brain–heart infusion agar, incubated aerobically and anaerobically at 37°C, and on Sabouraud dextrose agar with 0.5% yeast extract, incubated aerobically at 37°C and room temperature. The specimen for culture should be taken from a deep site, preferably from the base of a biopsy. Cultures should be processed by a reference laboratory and should not be grown in an office laboratory.


Mycetoma may be diagnosed by keeping in mind a triad of signs, namely: tumefaction, sinuses, and granules. Pus gathered from a deep sinus will show the granules when examined with the microscope. The slide containing the specimen should have a drop of 10% NaOH added and a coverslip placed on top. A biopsy may be required. Radiographs will show the bone involvement and MRI images may show the “dot in a circle” sign, corresponding to grains.


Actinomycetomas generally respond to antibiotic therapy, although advanced cases may also need surgery. In A. israelii infection, penicillin in large doses is curative. N. asteroides or N. brasiliensis is usually treated with sulfonamides. A combination of rifampicin and co-trimoxazole has also been used. Severe refractory disease may respond to imipenem.

Patients in the early stage of eumycetoma may be successfully treated by surgical removal of the area. In the more advanced stages, a combination of antifungal therapy and surgery may be successful. In some cases of eumycetoma, amputation will be necessary. Surgical excision combined with itraconazole, 200 mg twice a day until clinically well, may be effective in cases caused by P. boydii. P. boydii is not generally responsive to amphotericin, although liposome-encapsulated forms may have an effect. In one study, 30 isolates of P. boydii were tested for activity of posaconazole, fluconazole, and itraconazole in a mouse model of disseminated disease. Posaconazole was as effective as fluconazole and more effective than itraconazole.


Rhinosporidiosis is a polypoid disease usually involving mucosal surfaces, especially the nasal mucosa (Fig. 15-31). Conjunctival, lacrimal, oral, and urethral tissues may also be involved, and genital lesions may resemble condylomata. The lesions begin as small papillomas and develop into pedunculated tumors with fissured and warty surfaces. Grayish-white flecks may be noted on the tissue, corresponding to transepithelial elimination of large sporangia. Bleeding occurs easily. Disseminated cutaneous lesions are rare. Conjunctival lesions begin as small, pinkish papillary nodules. Later they become larger, dark, and lobulated. Rectal and vaginal lesions have been reported. Like penile lesions, they may resemble condylomata or polyps. Widespread dissemination rarely occurs, and bone involvement has been described. The disease is endemic in Sri Lanka and India, but also occurs in parts of East Asia and in Latin America. It has been seen in the southern US, the UK, and Italy.

Rhinosporidium seeberi, an organism found in stagnant water, is the causative organism. It has been characterized as either a fungus or protist. The organisms appear as spherules 7–10 µm in diameter, which are contained within large cystic sporangia that may be as large as 300 µm in diameter. When the organism does not form endospores, it resembles C. immitis spherules, but differs by the regular presence of a central nucleus within each organism. The organisms are usually present within a polypoid structure. A granulomatous response is seen in about 50% of cases, and gigantic foreign body giant cells can rarely be noted filled with organisms.

Suppurative inflammation may be observed at the site of rupture of sporangia. Transepithelial elimination of sporangia is common. Destruction of the involved area by excision or electrosurgery is the most common method of treatment. Antifungal agents have been of little value. Culture of the organism is easiest when it is grown together with the cyanobacterium Microcystis aeruginosa. These are unicellular prokaryotic organisms found in pond water together with R. seeberi. The two organisms have also been shown to grow together in tissue, suggesting that rhinosporidiosis may represent a synergistic infection of the fungus and cyanobacterium. As drugs such as ciprofloxacin are active against M. aeruginosa, trials of antibiotic therapy may be of value.











Categories: 15 )Fungus, yeast

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